The invention in its broad aspects relates to sulfoxide and sulfone derivatives of bicyclic lactams which are useful as converting enzyme inhibitors and as antihypertensives. The compounds of this invention are represented by the following formula: ##STR1## wherein: X is SO or SO.sub.2 ;
R and R.sub.2 are independently hydrogen, loweralkyl, aryl, and aralkyl; PA0 R.sub.1 is hydrogen; PA0 X is SO or SO.sub.2 ; PA0 R and R.sub.2 are hydrogen, loweralkyl, aryl or aralkyl; and PA0 R.sub.1 is alkyl of 1-10 carbon atoms which include branched, cyclic and unsaturated alkyl groups; PA0 X is SO or SO.sub.2 ; PA0 R and R.sub.2 are independently hydrogen, loweralkyl, aryl, or aralkyl; and, PA0 R.sub.1 is alkyl of 1-10 carbon atoms which include branched alkyl groups; PA0 X is SO or SO.sub.2 ; PA0 R and R.sub.2 are independently hydrogen, lower alkyl of 1 to 4 carbon atoms, phenyl, or benzyl; and, PA0 R.sub.1 is alkyl of 1-8 carbon atoms which include branched alkyl groups;
straight chain and branched alkyl, alkenyl, and alkynyl of from 1 to 12 carbon atoms (such as 3-methyl-1-butyl, 3,3-dimethylallyl, and the like); PA1 cycloalkyl of 3 to 10 carbon atoms; PA1 substituted lower alkyl wherein the substituent can be halo, hydroxy, carboxy, lower alkylthio, lower alkoxy, lower alkoxy carbonyl, lower aralkoxy carbonyl, amino, lower alkylamino, lower dialkylamino, or acylamino; PA1 substituted lower alkyl having the formula R.sub.A (CH.sub.2).sub.n --Q--(CH.sub.2).sub.m wherein n is 0-2, m is 1-3, R.sub.A is aryl or heteroaryl optionally substituted by amino, lower dialkylamino, lower alkylamino, hydroxy, hydroxy loweralkyl, aminoloweralkyl, trihaloloweralkyl, cyano, nitro, sulfonamido, aroyl, lower alkyl, halo, dihalo, and lower alkoxy, and Q is O, S, N-R.sub.B, CONR.sub.C, NR.sub.C CO, CH.dbd.CH wherein R.sub.B is hydrogen, loweralkyl, aryl, aralkyl, lower alkanoyl, or aroyl, and R.sub.C is hydrogen or lower alkyl; PA1 aryl (such as phenyl, naphthyl or biphenyl); PA1 substituted aryl wherein the substituent is lower alkyl, amino loweralkyl, loweralkoxy, aryloxy, aroyl, hydroxy, halo, or dihalo; PA1 aralkyl or heteroaralkyl which include branched lower alkyl groups (such as 2,2-dibenzylethyl); PA1 substituted aralkyl or substituted heteroaralkyl which include branched lower alkyl groups wherein the lower alkyl groups can be substituted by amino, acylamino, or hydroxyl and the aryl and heteroaryl groups can be substituted by halo, dihalo, loweralkyl, hydroxy, loweralkoxy, aryloxy, aroyl, arylthio, amino, amino lower alkyl, lower alkanoylamino, aroylamino, lower dialkylamino, lower alkylamino, hydroxy, hydroxy loweralkyl, trihalo loweralkyl, nitro, cyano, or sulfonamido; and, PA1 substituted loweralkyl wherein the substituent can be hydroxy, lower alkylthio, amino, alkylamino, lower dialkylamino, and acylamino; PA1 substituted lower alkyl having the formula R.sub.A (CH.sub.2).sub.n --Q--(CH.sub.2).sub.m--wherein n is 0-2, m is 1-3, R.sub.A is aryl or heteroaryl optionally substituted by alkyl, halo, dihalo, amino, cyano, hydroxy, or alkoxy, and Q is O, S, N--R.sub.B, CONR.sub.C, NR.sub.C CO, or CH.dbd.CH wherein R.sub.B is hydrogen, lower alkyl, aralkyl, lower alkanoyl, or aroyl and R.sub.C is hydrogen or lower alkyl; aralkyl or heteroaralkyl which include branched lower alkyl groups; PA1 substituted aralkyl or substituted heteroaralkyl which include branched lower alkyl groups wherein the lower alkyl substituents can be amino, acylamino, or hydroxy and the aryl and heteroaryl substituents can be lower alkyl, halo, dihalo, amino, cyano, hydroxy, lower alkoxy, amino loweralkyl, or hydroxyloweralkyl. PA1 substituted lower alkyl wherein the substituent can be amino, acylamino, or lower alkylthio; PA1 substituted lower alkyl having the formula R.sub.A (CH.sub.2).sub.n --Q--(CH.sub.2).sub.m --wherein n is 0-1, m is 1-2, R.sub.A is phenyl optionally substituted by halo, dihalo, alkoxy, or cyano, and Q is O or S; aralkyl or heteroaralkyl; PA1 substituted aralkyl or substituted heteroaralkyl wherein the aryl and heteroaryl substituents are halo, dihalo, cyano, hydroxy, hydroxy lower alkyl, amino, and amino lower alkyl. PA1 substituted lower alkyl wherein the substituent can be amino or loweralkylthio; substituted lower alkyl having the formula R.sub.A (CH.sub.2).sub.n --Q--(CH.sub.2).sub.m --wherein n is O, m is 1, R.sub.A is phenyl, and Q is O or S; aralkyl wherein the aryl is phenyl or naphthyl and the alkyl group contains 1 to 3 carbon atoms, or heteroaralkyl wherein the heteroaryl group is indole, thiophene, imidazole, pyridine, quinoline or isoquinoline and the alkyl group contains 1 to 3 carbon atoms; PA1 substituted aralkyl wherein the aryl is a phenyl group, the alkyl contains 1 to 3 carbon atoms, and the phenyl substituents can be halo, hydroxy, phenoxy, lower alkoxy, amino, or aminomethyl.
the pharmaceutically acceptable salts thereof.
The lower alkyl groups, except where noted otherwise, represented by any of the variables include straight and branched chain hydrocarbon radicals from one to six carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl or vinyl, allyl, butenyl and the like. The aralkyl and heteroaralkyl groups represented by any of the above variables have from one to six carbon atoms in the alkyl portion thereof and include for example, benzyl, phenethyl, 3,3-diphenylpropyl, 3-indolylmethyl, and the like. Halo means chloro, bromo, iodo or fluoro. Aryl and the prefix "ar" where they appear in any of the radicals, except where noted, have 5-6 ring atoms such as, for example, phenyl, naphthyl, or biphenyl. Aroyl includes benzoyl, 1-naphthoyl, and the like. Heteroaryl includes, for example, indolyl, thienyl, imidazolyl, furyl, benzimidazolyl, pyridyl, quinolinyl, isoquinolinyl, and benzothienyl. Acylamino refers to lower alkanoylamino and aroylamino groups such as, for example, acetylamino, benzoylamino, and the like. Hetero denotes one of the heteroatoms N, O or S.
Preferred are those compounds of Formula I wherein:
Still more preferred are those compounds of Formula I wherein:
Most preferred are compounds of Formula I wherein:
The preferred, more preferred and most preferred compounds also include the pharmaceutically acceptable salts thereof.
The products of Formula I can be prepared according to the methods described hereinbelow in Reaction Schemes I-IV wherein R, R.sub.1 and R.sub.2 are as defined above unless otherwise specified.
As shown in Reaction Scheme I below, preferred products of Formula I can be produced from bicyclic lactam II. Treatment of bicyclic lactam II in which the amine is protected as a hydrochloride salt with one equivalent of an oxidizing agent, such as m-chloroperoxybenzoic acid, produces compounds I' where X=SO. Since the sulfoxide center represents a new chiral center, two diastereomeric sulfoxides are possible. Reaction of II with an excess of oxidant affords compounds I" where X=SO.sub.2. Treatment of I' where X=SO with an excess of an oxidizing agent also affords compounds I" where X=SO.sub.2. ##STR2##
The preferred bicyclic lactam structure (II) can be produced according to the procedures disclosed in European Patent Application No. 82,102,330.6 which is incorporated herein by reference, or by the novel procedure illustrated in Reaction Scheme II below. In this new process, the known commercially available starting material, N.sub..epsilon. -t-BOC-L-lysine (III) is first reacted with N-carbethoxyphthalimide and then with trifluoroacetic acid to produce IV. Condensation of IV with the known 4-formyl-1-methylpyridinium benzenesulfonate [T. F. Buckley, et al., J. Am. Chem. Soc., 104, 4446-50 (1982)] produces a Schiff base which is equilibrated to V by the addition of base (1,8-diazabicyclo[5.4.0]undec-7-ene) (DBU). Addition of one equivalent of an ester of R-cysteine, hydrochloride to V forms a diastereomeric mixture of thiazolidines VI. Cyclization to the preferred bicyclic lactam diastereomers VIIa (S,R,R diastereomer) and VIIb (S,S,R diastereomer) (1:1 ratio) is achieved with N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) or N-isobutoxycarbonyl-2-isobutoxy-1,2-dihydroquinoline (IIDQ). Diastereomers VIIa and VIIb can be separated by column chromatography.
The more preferred diastereomer VIIa can also be obtained by treating VIIb or a mixture of VIIa and VIIb with a strong acid, such as p-toluenesulfonic acid or Amberlyst 15 resin in benzene at reflux. This establishes an equilibrium between VIIb and VIIa in which VIIa predominates by a large margin. (Weight ratio of VIIa:VIIb is about 96:4.) Treatment of VIIa and VIIb with hydrazine gives the amino lactams VIIIa and VIIIb, respectively. Lactam VIIIb can be equilibrated to VIIIa by a similar acid treatment such as, for example, with trifluoroacetic acid. The ester group can then be removed with dilute alkali or, in the case R.sub.2 =CH.sub.2 Ph, by hydrogenolysis to yield the acids (R.sub.2 =H) of VIIIa and VIIIb. ##STR3##
As summarized in Reaction Scheme III below, products of Formula II can be prepared from the diastereomeric mixture of amino cyclic lactams VIII or from diastereomerically pure compounds VIIIa and VIIIb by reductive alkylation of these intermediates with .alpha.-keto acids or .alpha.-keto esters IX. In these alkylations, one typically uses sodium cyanoborohydride under neutral conditions, but it is also possible to employ hydrides bearing optically active ligands or sterically bulky ligands selected to improve the stereochemical control in these reductions. These reductive alkylations can also be achieved by catalytic hydrogenation over 10% palladium on carbon or other suitable catalysts.
As also summarized in Reaction Scheme III, products of Formula I can be prepared from the diastereomeric mixture of IIa, IIb or from diastereomerically pure IIa or IIb. In general, the amine functionality is protected as an acid salt, such as its hydrochloride salt, during the oxidation of IIa/b to products of Formula Ia or Ib where X=SO or SO.sub.2. In the case where X=SO, a new asymmetric center is created at the sulfur and, consequently, diastereomers at this center are possible, in which case they can be employed as a mixture of diastereomers or separated and used as pure diastereomers. ##STR4##
In Reaction Scheme IV which follows, an alternative route to compounds of Formula I is shown which involves a variation in the sequence of the reactions utilized in Reaction Schemes II and III. In Reaction Scheme IV, oxidation of the sulfide in intermediates VII or VIII is accomplished with removal of protecting groups, if any, prior to the reductive alkylation reaction with .alpha.-keto acids or .alpha.-keto esters, IX. By this procedure, R.sub.1 side chains containing functionality susceptible to oxidation (for example, when R.sub.1 is .phi.CH.sub.2 SCH.sub.2 --) can be introduced to give products of Formula I. ##STR5##
Intermediate VIII has three asymmetric carbon atoms: one bears the NH.sub.2 group; another is that bearing the hydrogen at the ring juncture; and, a third is that bearing the CO2R.sub.2 group. The preferred absolute configuration at these centers are 6(S), 9a(R), 3(R)(VIIIa) and 6(S), 9a(S), 3(R)(VIIIb). When X=SO, intermediate XI has, in addition to the three asymmetric centers described for VIII, a fourth center at the sulfur which can have R and S absolute configurations.
In Formula I compounds, the carbon atom bearing R.sub.1 is also asymmetric (R.sub.1 .noteq.H). Both isomers in this position have some biological activity, although the natural L-aminoacid configuration is preferred. In most cases, the absolute configuration at this center is designated (S).
Preferred diastereomers are isolated by chromatography or crystallization of intermediates or the end products or their salts. One can also resolve intermediates by the use of optically active salts or bases. Finally, if desired, compounds of this invention can also be employed as a mixture of their enantiomers or diastereomers.
The .alpha.-keto acids and .alpha.-keto esters IX utilized in the process of the invention are known in the art or can be made by numerous, known methods. For example, synthons such as ##STR6## can be converted to o-keto acids or esters using methods involving alkylation followed by hydrolysis as described in the literature. An excellent method involves the reaction of Grignard reagents R.sub.1 MgX with ClCOCO.sub.2 Y or YO.sub.2 CCO.sub.2 Y. Another method involves condensing substituted acetic acid esters with diethyl oxalate followed by hydrolytic decarboxylation under acidic conditions to obtain .alpha.-keto acids. Carefully controlled acid hydrolysis in alcohol of acyl cyanides, which are prepared from acid chlorides and cuprous cyanide, also proves to be a viable synthetic route to .alpha.-keto esters. Nucleophilic displacement reactions on chloro or bromo pyruvic acid (ester) can also be used to produce a variety of interesting .alpha.-keto acids (esters). In these formulae, Y is a group such as loweralkyl or benzyl and protecting groups are employed as necessary in the R.sub.1 group if interfering functionality is present.
The compounds of this invention form salts with various inorganic and organic acids and bases which are also within the scope of the invention. Such salts include ammonium salts, alkali metal salts like sodium and potassium salts, alkaline earth metal salts like the calcium and magnesium salts, salts with organic bases e.g., dicyclohexylamine salts, N-methyl-D-glucamine, salts with amino acids like arginine, lysine and the like. Also salts with organic and inorganic acids may be prepared, e.g., HCl, HBr, H.sub.2 SO.sub.4, H.sub.3 PO.sub.4, methanesulfonic, toluenesulfonic, maleic, fumaric, camphorsulfonic. The non-toxic physiologically acceptable salts are preferred, although other salts are also useful, e.g., in isolating or purifying the product.
The salts may be formed by conventional means as by reacting the free acid or free base forms of the product with one or more equivalents of the appropriate base or acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is then removed in vacuo or by freeze-drying or by exchanging the cations of an existing salt for another cation on a suitable ion exchange resin.
The compounds of this invention inhibit angiotensin converting enzyme and thus block conversion of the decapeptide angiotensin I to angiotensin II. Angiotensin II is a potent pressor substance. Thus, blood-pressure lowering can result from inhibition of its biosynthesis especially in animals and humans whose hypertension is angiotensin II related. Furthermore, converting enzyme degrades the vasodepressor substance, bradykinin. Tnerefore, inhibitors of angiotensin converting enzyme may lower blood-pressure also by potentiation of bradykinin. Although the relative importance of these and other possible mechanisms remains to be established, inhibitors of angiotensin converting enzyme are effective antihypertensive agents in a variety of animal models and are useful clinically, for example, in many human patients with renovascular, malignant and essential hypertension. See, for example, D. W. Cushman et al., Biochemistry 16, 5484 (1977).
The evaluation of converting enzyme inhibitors is guided by in vitro enzyme inhibition assays. For example, a useful method is that of Y. Piquilloud, A. Reinharz and M. Roth, Biochem. Biophys. Acta, 206, 136 (1970) in which the hydrolysis of carbobenzyloxyphenylalanylhistidinylleucine is measured. In vivo evaluations may be made, for example, in normotensive rats challenged with angiotensin I by the technique of J.R. Weeks and J.A. Jones, Proc. Soc. Exp. Biol. Med., 104, 646 (1960) or in a high renin rat model such as that of S. Koletsky et al., Proc. Soc. Exp. Biol. Med. 125, 96 (1967).
Thus, the compounds of this invention are useful as antihypertensives in treating hypertensive mammals, including humans, and they can be utilized to achieve the reduction of blood pressure by formulating in compositions such as tablets, capsules or elixirs for oral administration or in sterile solutions or suspensions for parenteral administration. The compounds of this invention can be administered to patients in need of such treatment in a dosage range of 0.5 to 100 mg per patient generally given several times, thus giving a total daily dose of from 0.5 to 400 mg per day. The dose will vary depending on severity of disease, weight of patient and other factors which a person skilled in the art will recognize.
It is often advantageous to administer compounds of this invention in combination with other antihypertensives and/or diuretics. For example, the compounds of this invention can be given in combination with such compounds as amiloride, atenolol, bendroflumethiazide, chlorothalidone, chlorothiazide, clonidine, cryptenamine acetate and cryptenamine tannates, deserpidine, diazoxide, ethacrynic acid, furosemide, guanethidene sulfate, hydralazine hydrochloride, hydrochlorothiazide, hydroflumethiazide, metolazone, metoprolol tartate, methyclothiazide, methyldopa, methyldopate hydrochloride, minoxidil, (S)-1-{[2-(3,4-dimethoxyphenyl)ethyl]amino}-3-{[4-(2-thienyl)-1H-imidazol- 2-yl]phenox}-2-propanol, polythiazide, the pivaloyloxyethyl ester of methyldopa, indacrinone and variable ratios of its enantiomers, nifedipine, verapamil, diltiazam, flumethiazide, bendroflumethiazide, atenolol, (+)-4-{3-}-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl{propy}benz oic acid, bumetanide, prazosin, propranolol, rauwolfia serpentina, rescinnamine, reserpine, spironolactone, timolol, trichlormethiazide, benzthiazide, quinethazone, tricrynafan, triamterene, acetazolamide, aminophylline, cyclothiazide, merethoxylline procaine, and the like, as well as admixtures and combinations thereof.
Typically, the individual daily dosages for these combinations can range from about one-fifth of the minimally recommended clinical dosages to the maximum recommended levels for the entities when they are given singly.
To illustrate these combinations, one of the antihypertensives of this invention effective clinically in the 0.5-100 milligrams per day range can be effectively combined at levels at the 0.1-100 milligrams per day range with the following compounds at the indicated per day dose range: hydrochlorothiazide (10-100 mg), timolol (5-60 mg), methyldopa (65-2000 mg), the pivaloyloxyethyl ester of methyldopa (30-1000 mg), indacrinone and variable ratios of its enantiomers (25-150 mg) and (+)-4-{3-[2-(1hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}-benzo ic acid (10-100 mg).
In addition, the triple drug combinations of hydrochlorothiazide (10-100 mg) plus timolol (5-60 mg) plus converting enzyme inhibitor of this invention (0.5-100 mg) or hydrochlorothiazide (10-100 mg) plus amiloride (5-20 mg) plus converting enzyme inhibitor of this invention (0.5-100 mg) are effective combinations to control blood pressure in hypertensive patients. Naturally, these dose ranges can be adjusted on a unit basis as necessary to permit divided daily dosage and, as noted above, the dose will vary depending on the nature and severity of the disease, weight of patient, special diets and other factors.
Typically, the combinations shown above are formulated into pharmaceutical compositions as discussed below.
About 0.1 to 50 mg of a compound or mixture of compounds of Formula I or a physiologically acceptable salt is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in a unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance in these compositions or preparations is such that a suitable dosage in the range indicated is obtained.
Illustrative of the adjuvants which may be incorporated in tablets, capsules, and the like are the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient such as microcrystalline cellulose; a disintegrating agent such as corn starch, pregelatinized starch, alginic acid and the like; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, lactose or saccharin; a flavoring agent such as peppermint, oil of wintergreen or cherry. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as fatty oil. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
Sterile compositions for injection can be formulated according to conventional pharmaceutical practice by dissolving or suspending the active substance in a vehicle such as water for injection, a naturally occurring vegetable oil like sesame oil, coconut oil, peanut oil, cottonseed oil, etc. or a synthetic fatty vehicle like ethyl oleate or the like. Buffers, preservatives, antioxidants and the like can be incorporated as required.